PROJECT SUMMARY In the parent grant, we proposed to study a cellular mechanism underlying age-related cognitive dysfunction, a likely risk factor of postoperative cognitive dysfunction (POCD) and to develop pharmacological interventions to prevent or to reverse POCD. The molecular and cellular mechanisms underlying POCD are unknown, as is the reason why POCD occurs more frequently in elderly patients than in younger patients. As POCD increases with age, age-related cognitive dysfunction likely represents a risk factor. It has been shown in rodents that loss of somatostatin-positive interneurons in the dentate gyrus (DG) hilus results in hyperexcitability of DG and CA3 and is associated with age-related cognitive dysfunction. However, a cause-effect relationship between loss of somatostatin-positive interneurons in the DG hilus and cognitive dysfunction has not been demonstrated so far. We therefore want to chemogenetically inhibit and genetically ablate these neurons to demonstrate that these changes are sufficient to elicit cognitive dysfunction. Moreover, we want to pharmacologically reverse these deficits and identify the molecular and cellular basis for this reversal. It has been reported that in aged rats but not in young rats a GABAA receptor ?5-positive allosteric modulator (?5-PAM) improves cognitive function, which is in line with an ?5-PAM reducing the hyperexcitability of DG and CA3 of the hippocampus in aged rats. It has also been reported that chronic intermittent propofol improves age-related cognitive dysfunction, but the molecular and cellular substrates of this action have not been identified. We want to test the hypothesis that this action of propofol is mediated by a sustained increase in expression of ?5-containing GABAA receptors on the cell surface. We also want to identify the neuronal cell population expressing the ?5-containing GABAA receptors that mediate this improvement of cognition. Furthermore, we want to test whether chemogenetic inhibition of somatostatin-positive interneurons in the DG hilus of young adult mice is sufficient to elicit the cognitive- enhancing effect of chronic intermittent propofol. Finally, we will study whether postoperative (i.e., post laparotomy) impairment of cognitive function can be prevented or reduced by chronic intermittent propofol or a GABAA receptor ?5-PAM. The work described in the parent grant requires preparation of mouse brain sections, e.g., for c-fos staining and immunohistochemistry. The outdated (30 year old) cryostat currently available in the department makes it difficult to efficiently obtain high-quality slices. Here we request funds for replacing the existing cryostat with a cryostat from Hacker Instruments/Industries, Inc..